2,4-Thiazolidinedione Derivatives in the Treatment of Central Nervous System Disorders

ABSTRACT

The present invention provides 5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione and novel stereoisomers of said compound for use in the treatment of central nervous system (NS) disorders.

FIELD OF THE INVENTION

This invention relates to novel uses of 2,4-thiazolidinedionederivatives as medicaments in particular for the treatment of centralnervous system disorders.

BACKGROUND OF THE INVENTION

Central Nervous System (NS) disorders are diseases of any component ofthe brain and the spinal cord. NS disorders include disorders in whichthe nervous system is affected during the entire progression of thediseases such as neurodegenerative diseases (e.g., Alzheimer's disease,Huntington's chorea, Parkinson's disease, amyotrophic lateral sclerosis(ALS), degenerative ataxias such as Friedrich's ataxia, multiplesclerosis, multiple system atrophy and leukodystrophies),cerebrovascular diseases (e.g., global or local ischemia, intracerebralhaemorrhage, stroke), seizures and epilepsy, viral diseases (e.g.,meningitis, encephalitis), brain tumors and neuroinflammatory diseases.NS disorders also include disorders in which the nervous system is onlyaffected during the latest stages of the development of the disorder.These disorders comprise rare metabolic diseases such as organicacidemias or fatty acid disorders and genetic mitochondrial disorders.

Neurodegenerative diseases are characterised by the progressive loss ofstructure or function of neurons, including death of neurons. Theseconditions are progressive and often fatal. The process ofneurodegeneration is not well understood and the diseases that stem fromit have, as yet, no cures in spite of treatments being constantlysought.

Some neurodegenerative diseases also include an inflammatory componentsuch as multiple sclerosis which traditionally was considered asinflammatory mediated demyelinating diseases but, in fact, is aneurodegenerative disease in which axonal damage, neuronal death andatrophy of the central NS are the principal causes of irreversibleneurological disability in patients. Thus, multiple sclerosis can beconsidered as a neurodegenerative disease but also as aneuroinflammatory disease or autoimmune disease.

Leukodystrophies are a group of generic NS disorders whose main featureis the degeneration of the white matter in the brain. One disorder ofthis group is adrenoleukodystrophy (X-linked adrenoleukodystrophy orX-ALD). This is a rare, inherited disorder that leads to progressivedamage to the brain and other tissues and eventually death. This diseasecan be considered both as neurodegenerative and neuroinflammatory.

X-ALD presents three main phenotypes: (i) an adult adrenomyeloneuropathy(AMN) with axonopathy in spinal cords. (ii) cerebraladrenomyeloneuropathy with brain demyelination (cAMN), and (iii)childhood variant (cALD) characterized by severe cerebral demyelination.X-ALD is the most frequently inherited leukodystrophy, with a minimumincidence of 1 in 17,000 including hemizygous males and carrier females.

Cerebrovascular diseases are a group of brain dysfunctions related todisease of the blood vessels supplying the brain. There are four types:stroke, transient ischaemic attack (TIA), subarachnoid haemorrhage andvascular dementia.

Epilepsy is an unpredictable, serious and potentially fatal disorder ofthe nervous system. About 50 million people worldwide have epilepsy.

Brain tumours are generated by an abnormal and uncontrolled celldivision not only in the brain (neurons or glial cells) but also inblood vessels, cranial nerves, meninges, skull, and pituitary or pinealglands. Brain tumours also include those that have spread from primarycancer cells located in other organs (metastasis).

Nervous system viral diseases are caused by viral infections in the NS.These infections can induce neurological dysfunction and potentiallyserious inflammatory diseases such as encephalitis, an inflammation ofthe brain itself, meningitis that results in inflammation of themeninges or myelitis that means spinal cord inflammation. Rabies,measles, mumps, poliomyelitis, herpes simplex or varicella-zoster aretypes of nervous system viral infections.

Rare metabolic diseases (also known as Inborn Errors of Metabolism) areusually monogenic diseases where certain metabolic pathways areperturbed thus originating dysfunctions, in many cases on the centralNS. They are chronically debilitating and life-threatening conditions.

Genetic mitochondrial diseases can be caused by mutations in eithermtDNA or nDNA, that impair mitochondrial function and typically resultin very severe multisystem disease from birth, including severemanifestations on the NS.

There is an urgent need for new treatments of central NS disorders.

A wide variety of deuterium enriched 2,4-thiazolidinediones have beendescribed in US 2014/0275180. This document also discloses theirprophetic use in the treatment of a variety of different diseases.However, this document fails to provide any evidence in this regard orregarding the ability of these compounds to cross the blood-brainbarrier (BBB).

Pioglitazone is a drug marketed for use in the treatment of diabetesmellitus type 2. Pioglitazone is a potent agonist for peroxisomeproliferator-activated receptor-gamma (PPARγ) and it has been proposedfor the treatment of some neurodegenerative diseases includingAlzheimer's, Parkinson's disease, ALS and Friedreich's ataxia.US2013/0274295 discloses the utility of Pioglitazone in the treatment ofX-ALD based on pre-clinical data. Although pre-clinical models haveshown promising results, clinical trials to date have failed to showclinical benefits in any of these extremely serious conditions.

In addition, Pioglitazone has been associated with unwanted side effectsincluding cardiovascular effects, fluid retention, weight gain andbladder cancer. High doses of Pioglitazone are therefore undesirable ashigh systemic exposure would be likely to result in serious sideeffects.

Pioglitazone is a “dirty” drug which is converted to many metabolites invivo. The metabolic pathway of Pioglitazone after oral administrationhas been studied in several animal species and in humans and themetabolites have been described in the literature (see e.g. Sohda et al,Chem. Pharm. Bull., 1995, 43(12), 2168-2172) and Maeshiba et al,Arzneim.-Forsch/Drug Res, 1997, 47 (I), 29-35). At least six metaboliteshave been identified, named M-I to M-VI. Amongst these metabolites,M-II, M-III and M-IV show some pharmacological activity but are lessactive than Pioglitazone in diabetic preclinical models.

The distribution of Pioglitazone and its metabolites in various tissuesafter oral administration of [¹⁴C]-Pioglitazone to rats has also beenstudied (Maeshiba et al, Arzneim.-Forsch/Drug Res, 1997, 47 (i), 29-35).In most tissues the concentrations of Pioglitazone and metabolites M-Ito M-VI were lower than that in plasma and one of the lowestconcentrations of radioactivity was found in the brain where onlyPioglitazone was mainly detected.

SUMMARY OF THE INVENTION

Surprisingly it has been found that central NS disorders can be treatedby 5-[4-[2-(5-(1-hydroxyethyl)-2-pyridinyl)ethoxy]benzyl]-2,4-thiazolidinedione of formula (1), the M-IV metabolite of Pioglitazone.

or a salt thereof.

The NS disorders include, but are not limited to, disorders in which thenervous system is affected during the entire progression of the diseasessuch as neurodegenerative diseases (e.g., Alzheimer's disease,Huntington's chorea, Parkinson's disease, amyotrophic lateral sclerosis(ALS), degenerative ataxias, multiple system atrophy andleukodystrophies), cerebrovascular diseases (e.g., global or localischemia, intracerebral hemorrhage, stroke), seizures and epilepsy,viral diseases (e.g., meningitis, encephalitis), multiple sclerosis,brain tumors, and injury. NS disorders also include disorders in whichthe nervous system is only affected in the latest stages of thedevelopment of the condition and include rare metabolic diseases such asorganic acidemias or fatty acid disorders and genetic mitochondrialdisorders.

The invention is based at least in part on data showing the unexpectedability of the compound of formula (1) to cross the blood brain barrier.In addition, the compound of the invention has one or more desirabledrug properties such as good oral bioavailability, low systemic plasmaclearance, and a good volume of distribution. Furthermore, the compoundof the invention is a reasonably “clean” drug, since in vivo it onlyconverts to5-(4-(2-(5-acetyl-2-pyridyl)ethoxy)benzyl)-2,4-thiazolidinedione (M-IIImetabolite of Pioglitazone) and both are excreted. Side effects due tounwanted metabolites are therefore minimised.

Thus, according to an aspect of the invention, there is provided acompound of formula (1) or pharmaceutically acceptable salts thereof ormixture of compounds of formula (1) for use as a medicament inparticular for the treatment or prevention of central NS disorders.According to another aspect, the invention provides the use of acompound of formula (1) or pharmaceutically acceptable salts thereof ormixture of compounds of formula (1) for the manufacture of a medicamentin particular for the treatment or prevention of central NS disorders.According to another aspect, the invention provides a method for thetreatment or prevention of a disease of central NS comprisingadministering to a subject in need thereof an effective amount of acompound of formula (1) or pharmaceutically acceptable salts thereof ormixture of compounds of formula (1). According to another aspect of theinvention there are provided pharmaceutical compositions comprising acompound of formula (1) or pharmaceutically acceptable salts thereof ormixtures of compounds of formula (1).

According to another aspect the present invention provides novelcompounds (2) to (5):

-   -   (2)        (R)-5-(4-(2-(5-((R)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione    -   (3)        (R)-5-(4-(2-(5-((S)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione    -   (4)        (S)-5-(4-(2-(5-((R)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione    -   (5)        (S)-5-(4-(2-(5-((S)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione    -   or a pharmaceutically acceptable salt thereof.

According to still another aspect the present invention providesmixtures of one or more of the compounds (2) to (5) or pharmaceuticallyacceptable salts thereof for use in the treatment or prevention ofcentral nervous system disorders. According to another aspect, theinvention provides the use of one or more of the compounds (2) to (5) orpharmaceutically acceptable salts thereof for the manufacture of amedicament for the treatment or prevention of central NS disorders.According to another aspect, the invention provides a method for thetreatment or prevention of a disease of central NS comprisingadministering to a subject in need thereof an effective amount of one ormore of the compounds (2) to (5) or pharmaceutically acceptable saltsthereof.

In yet another aspect the invention provides pharmaceutical compositionscomprising a one or more compounds of formulae (2) to (5) orpharmaceutically acceptable salts thereof, including mixtures ofcompounds of formula (2) to (5) for use in the treatment or preventionof central NS disorders.

In another aspect, the invention provides a method tor treating orpreventing central nervous system disorders, including neurodegenerativediseases (such as Alzheimer's disease, Huntington's chorea, Parkinson'sdisease, amyotrophic lateral sclerosis (ALS), degenerative ataxias,multiple system atrophy, multiple sclerosis and leukodystrophies such asALD), cerebrovascular diseases, seizures, epilepsy, viral diseases,brain tumours, neuroinflammatory diseases NS disorders that affect thenervous system in the latest stages of the development of the conditionincluding rare metabolic diseases such as organic acidemias or fattyacid disorders and genetic mitochondrial disorders through theadministration of a compound of formula (1) or a pharmaceuticallyacceptable salt thereof, or of one or more compounds of formulae (2) to(5) or pharmaceutically acceptable salts thereof.

DESCRIPTION OF THE FIGURES

FIG. 1 represents the concentration of compound of formula (1) in plasmaof a C57BL/6 mouse after a single intravenous administration of 1 mg/Kgof said compound.

FIG. 2 represents the concentrations of compound of formula (1) inplasma of a C57BL/6 mouse after a single oral administration of 4.5mg/Kg of said compound.

FIG. 3 represents the concentration of compound of formula (1) in braintissue of a C57BL/6 mouse after a single oral administration of 4.5mg/Kg of said compound (line with circle markers) and after a singleintravenous administration of 1 mg/Kg of said compound (line with squaremarkers).

FIG. 4 represents the brain plasma ration calculated based on levels ofPioglitazone, MIV, MIII and MII in plasma and brain quantified at Cmax(maximal concentration) following oral dosing of a single administrationof Pioglitazone at 4.5 mg/kg in male C57BL/6 mice.

FIG. 5 represents the brain plasma ration calculated based on thepharmacokinetics curves of plasma and brain concentration-time profilescalculated as area under the curves of Pioglitazone and following oraldosing of a single administration of either Pioglitazone or MIV both at4.5 mg/kg in male C57BL/6 mice.

FIG. 6 represents the concentrations of mixture (c) comprising compounds(2) and (4) and mixture (d) comprising compounds (3) and (5) in plasmaof a C57BL/6 mouse after a single oral administration of 4.5 mg/Kg ofsaid mixtures.

FIG. 7 represents the effect of compound of formula (1) in primary ratcortical neurons injured by glutamate.

FIG. 8 represents the effect of compound of formula (1) in primaryculture of sensory neurons injured by Paclitaxel (Taxol).

FIG. 9 represent the effect of compound of formula (1) in the disabilityscore in an in vivo efficacy study in an experimental autoimmuneencephalomyelitis (EAE) of multiple mouse model.

FIG. 10 represents the effect of compound of formula (1) in primarymotor neurons injured by glutamate.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention the terms “compound of formula (1)”, “M-IV”,“MIV” and “M4” indistinctively refer to5-[4-[2-(5-(1-hydroxyethyl)-2-pyridinyl)ethoxy]benzyl]-2,4-thiazolidinedione,which has the structure depicted above.

In one aspect, administration of compound of formula (1), or apharmaceutically acceptable salt is useful for the treatment orprevention of central NS disorders such as neurodegenerative diseases(e.g., Alzheimer's disease, Huntington's chorea, Parkinson's disease,amyotrophic lateral sclerosis (ALS), degenerative ataxias, multiplesystem atrophy, multiple sclerosis (MS) and leukodystrophies, such asadrenoleukodistrophy (ALD or X-ALD), cerebrovascular diseases (e.g.,global or local ischemia, intracerebral hemorrhage, stroke), seizuresand epilepsy, viral diseases (e.g., meningitis, encephalitis), braintumors and neuroinflammatory diseases, NS disorders also includedisorders in which the nervous system is only affected in the lateststages of the development of the disorder. These disorders comprise raremetabolic diseases such as organic acidemias or fatty acid disorders andgenetic mitochondrial disorders.

The term “treatment” or “to treat” in the context of this specificationmeans to ameliorate or eliminate the disease or one or more symptomsassociated with said disease. “Treatment” also encompasses amelioratingor eliminating the physiological sequelae of the disease.

The term “ameliorate” in the context of this invention is understood asmeaning any improvement on the situation of the patient treated.

The term “prevention” or “to prevent” refer to the reduction in the riskof acquiring or developing a given disease or disorder, or the reductionor inhibition of the recurrence or a disease or disorder.

The compound of formula (1) can be named5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dioneand has two chiral centres. One of them is the carbon atom in the5-position of the thiazolidine-dione ring and the other asymmetric atomis at position 1 of the hydroxyethyl group as shown by the arrows:

As used herein the term “compound of formula (1)” is used to designateall possible stereoisomers, including enantiomers and diastereomers, andmixtures including racemic mixtures thereof.

In another aspect, the invention provides novel compounds (2) to (5):

or pharmaceutical acceptable salts thereof.

Although compounds (2) to (5) have been prepared and isolated theirabsolute (R/S) configuration has not yet been determined and only theiroptical rotation has been determined.

Preferably, reference to compounds (1) to (5) in the present inventionis intended to designate compounds (1) to (5) having hydrogen atomswhich are predominantly in the form of its isotope ¹H, i.e. no more than1% of the total number of hydrogen atoms per mole of compound are in theform of the ²H isotope (deuterium), still more preferably no more than0.015% (which is the natural abundance of deuterium) of the total numberof hydrogen atoms per mole of compound are in the form of the ²H isotope(deuterium).

In a particular embodiment the following mixtures of compound (2) to (5)are preferred:

-   -   a) Mixtures comprising compounds (2) and (3), preferably being        compounds (2) and (3) the only compounds of formula (1) present        in the mixtures;    -   (b) Mixtures comprising (4) and (5), preferably being        compounds (4) and (5) the only compounds of formula (1) present        in the mixtures;    -   (c) Mixtures comprising (2) and (4), preferably being        compounds (2) and (4) the only compounds of formula (1) present        in the mixtures; and    -   (d) Mixtures comprising (3) and (5), preferably being        compounds (3) and (5) the only compounds of formula (1) present        in the mixtures.

Mixtures (c) and (d) are particularly preferred.

In the mixtures (a) to (d) mentioned above, it is particularly preferredthat the two compounds mentioned in each one of the mixtures are presentin equimolar quantities. Said mixtures may compound also minor amounts(preferably less than 10 wt. %. more preferably less than 3 wt %, stillmore preferably less than 1 wt. % and most preferably less than 0.1 wt.% of other compounds of formula (1).

Another aspect of the invention provides compounds (2) to (5) or apharmaceutically acceptable salt thereof or mixtures (a) to (d) orpharmaceutically acceptable salts thereof for use as medicaments. Thecompounds of the invention can be used to treat diseases such as centralnervous system disorders amongst others.

For use in the treatment of central NS disorders several factors may beconsidered when selecting a preferred compound. A compound showing highbrain-to-plasma exposure is preferred. A preferred compound displayspotent PPAR-gamma agonist activity but compounds with less potentPPAR-gamma agonist activity are also useful. Other factors, includingbut not limited to, pharmacological activity (other than PPAR-gamma),ADME, pharmacokinetic profile, toxicity, safety, brain distributionproperties, compound accumulation in tissues, compound metabolism andclearance, genotypic variation in clearance and physicochemicalproperties may also be considered for the selection of a preferredcompound. A preferred compound has low central nervous system toxicity.A preferred compound has low systemic toxicity. The presence or absenceof PPAR alpha activity may also be considered. In some cases it isdesirable for the compound to result in low or no accumulation in thebrain. This can reduce the risk of central nervous system toxicityand/or allow rapid reversal of drug effect in the central nervoussystem. In other cases, high brain accumulation with limited systemicexposure may be preferred. This can result in greater central nervoussystem exposure to the drug and higher efficacy. It is oftenadvantageous for the compound not to be the subject to significantgenotypic variations in clearance. This results in more consistentefficacy. These activities may be determined by use of the appropriatein vitro and in vivo assays.

In another aspect, the invention provides a method for treating orpreventing central NS disorders, including neurodegenerative diseases,cerebrovascular diseases, seizures, epilepsy, viral diseases, braintumours and neuroinflammatory diseases. The aspect also includes amethod for treating or preventing central NS disorders in which thenervous system is only affected in the latest stages of the developmentof the disorder include rare metabolic diseases such as organicacidemias or fatty acid disorders and genetic mitochondrial disorders bythe administration of a compound of formula (2) to (5) or apharmaceutically acceptable salt thereof or by administration of amixture of one or more compounds of formulae (2) to (5).

Another aspect of the present invention relates to the use of a compoundof formula (1) or a pharmaceutically acceptable salt thereof, or of oneor more compounds of formula (2) to (5) or pharmaceutically acceptablesalts thereof, or mixtures (a) to (d) or pharmaceutically acceptablesalts thereof, for the manufacture of a medicament for the treatment orprevention of central NS disorders, including neurodegenerativediseases, cerebrovascular diseases, seizures, epilepsy, viral diseases,brain tumours and neuroinflammatory diseases. The aspect also includesthe use of a compound of formula (1) or a pharmaceutically acceptablesalt thereof, or of one or more compounds of formula (2) to (5) orpharmaceutically acceptable salts thereof, or mixtures (a) to (d) orpharmaceutically acceptable salts thereof, for the manufacture of amedicament for the treatment or prevention of central NS disorders inwhich the nervous system is only affected in the latest stages of thedevelopment of the disorder include rare metabolic diseases such asorganic acidemias or fatty acid disorders and genetic mitochondrialdisorders.

Another aspect of the present invention relates a compound of formula(1) or a pharmaceutically acceptable salt thereof, or of one or morecompounds of formula (2) to (5) or pharmaceutically acceptable saltsthereof, or mixtures (a) to (d) or pharmaceutically acceptable saltsthereof, for use in the treatment or prevention of central NS disorders,including neurodegenerative diseases, cerebrovascular diseases,seizures, epilepsy, viral diseases, brain tumours and neuroinflammatorydiseases. The aspect also includes a compound of formula (1) or apharmaceutically acceptable salt thereof, or of one or more compounds offormula (2) to (5) or pharmaceutically acceptable salts thereof, ormixtures (a) to (d) or pharmaceutically acceptable salts thereof, foruse in the treatment or prevention of central NS disorders in which thenervous system is only affected in the latest stages of the developmentof the disorder include rare metabolic diseases such as organicacidemias or fatty acid disorders and genetic mitochondrial disorders.

In particular embodiments of the aspects of the invention describedabove, the disorder is selected from the group consisting ofneurodegenerative diseases, cerebrovascular diseases, seizures,epilepsy, viral diseases and brain tumours more preferably the disorderis a neurodegenerative disease; more preferably the disorder is selectedfrom the group consisting of Alzheimer's disease, Huntington's chorea,Parkinson's disease, Friedreich's ataxia, ALS multiple sclerosis, andX-ALD; more preferably the disorder is selected from the groupconsisting of Alzheimer's disease, Huntington's chorea, Parkinson'sdisease or multiple sclerosis; more preferably the disorder is multiplesclerosis; more preferably the disorder is a leukodystrophy such asadrenoleukodystrophy (ALD or X-ALD).

In other particular embodiments of the aspects of the inventiondescribed above, the disorder is a cerebrovascular disease.

A preferred compound or mixture of compounds may be selected for aparticular route of delivery. Some compounds or mixture of compounds mayalso be preferred based on their use to treat a particular disease.

The compounds of the invention can be in the form of a pharmaceuticallyacceptable salt. The term “pharmaceutically acceptable salt” refers tosalts prepared from pharmaceutically acceptable inorganic and organicacids.

Illustrative pharmaceutically acceptable acid addition salts of thecompounds of the present invention can be prepared from the followingacids, including without limitation, formic, acetic, propionic, benzoic,acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic,maleic, malic, tartaric, citric, nitric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric,hydrobromic, hydroiodic, isocitric, xinafoic, tartaric, trifluoroacetic,pamoic, propionic, anthranilic, mesylic, napadisylate, oxalacetic,oleic, stearic, salicylic, p-hydroxybenzoic, nicotinic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic,ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic,2-hydroxyethanesulfonic, sulfanilic, sulfuric, salicylic,cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric andgalacturonic acids. Exemplary pharmaceutically acceptable salts includethe salts of hydrochloric acid and hydrobromic acid.

The utility of the compound of formula (1), including stereoisomers (2)to (5), mixtures (a) to (d) and pharmaceutically acceptable salt thereofcan be demonstrated in appropriate in vitro or in vivo assays asdescribed in the examples.

The compounds of the invention or pharmaceutically acceptable salts maybe used according to the invention when the patient is also administeredor in combination with one or more of another therapeutic agent selectedfrom antiinflammatory and analgesic agents, dopamine agonists (e.g.levodopa), MAO-B inhibitors, catechol O-methyltransferase (COMT)inhibitors, anticholinergics, other antiparkinsonians (e.g. amantadine),antiNMDA receptors (e.g. memantine), cholinesterase inhibitors, ACEinhibitors, glutamate antagonist (e.g. riluzole), antioxidants,immunomodulators (e.g. fingolimod, anti CD52, CD25 and CD20 monoclonalantibodies, interferon-β-1a, natalizumab, laquinimod, dimethylfumarate)chemotherapeutics, enzyme replacement therapy agents, substratereduction therapy agents, corticosteroids, antiproliferatives (e.g.methotrexate), anticonvulsant medications, anticoagulants,antihypertensives and neuroprotectives. The compounds of the inventionmay also be used when the patient is undergoing gene therapy, bonemarrow transplantation, deep brain stimulation or radiotherapy.

Pharmaceutical compositions comprising compounds (2) to (5), mixtures(a) to (d) or a pharmaceutically acceptable salt represent anotheraspect of the invention. Any suitable route of administration can beused. For example, any of oral, intraoral, topical, epicutaneous,subcutaneous, transdermal, intramuscular, parenteral, ocular, rectal,vaginal, inhalation, buccal, sublingual and intranasal delivery routesmay be suitable. Oral administration may be preferred. Oral forms ofpharmaceutical compositions may be solid or liquid. Suitable dosageforms may be tablets, capsules, pills, granules, suspensions, emulsions,syrups or solutions. Preferably the pharmaceutical composition is asolid form selected from the group consisting of tablets, capsules,pills or granules. Particularly preferred are tablets. Oral solutions orsuspensions are also preferred. These are advantageous when the patienthas difficulty swallowing, for example as a result of the disease or forgeriatric and paediatric use. Sublingual preparations are alsoadvantageous.

By an “effective” amount or a “therapeutically effective amount” of adrug or pharmacologically active agent is meant a nontoxic butsufficient amount of the drug or agent to provide the desired effect.The amount that is “effective” will vary from subject to subject,depending on the age and general condition of the individual, theparticular active agent or agents, and the like. Thus, if is not alwayspossible to specify an exact “effective amount”. However, an appropriate“effective” amount in any individual case may be determined by one ofordinary skill in the art using routine experimentation. Thus, he doseof the active agent will depend on the nature and degree of thecondition, the age and condition of the patient, and other factors knownto those skilled in the art. A typical daily dosage is from 0.1 to 200mg, preferably from 20 to 200 mg, e.g. for an adult 10-100 mg given as asingle dose with no further dosing or in multiple doses, for example oneto three times per day. The compounds described herein may also beadministered in daily doses of from 80 to 600 mg.

The pharmaceutical compositions may contain conventional excipientsknown in the art and may be prepared by conventional methods.

The pharmaceutical compositions may further comprise one or moretherapeutic agent combination treatments may be administeredsimultaneously, sequentially or separately, by the same or by differentroutes, or before, during and after surgical or intervention procedures.

The compounds of the invention may be prepared by any suitable methodknown in the art and/or by the processes described below. It will alsobe appreciated that functional groups, such as amino or hydroxyl groups,present in the various compounds described, and which it is desired toretain, may need to be in protected form before any reaction isinitiated. In such instances, removal of the protecting group may be thefinal step in a particular reaction. Suitable protecting groups for suchfunctionality will be apparent to those skilled in the art. For specificdetails see “Protective Groups in Organic Synthesis”, WileyInterscience, T W Greene, PGM Wuts. Any mixtures of final products orintermediates obtained, can be separated on the basis of thephysicochemical differences of the constituents, in known manner, intothe pure final products or intermediates, for example by chromatography,distillation, fractional crystallization, or by formation of a salt ifappropriate or possible under the circumstances.

The compounds according to the invention may be prepared by thefollowing or similar processes.

Compound5-[4-[2-(5-(1-hydroxyethyl)-2-pyridinyl)ethoxy]benzyl]-2,4-thiazolidinedioneof formula (1) can be prepared according to Scheme 1 (see e.g. J. Med.Chem. 1996, 39(26),5053).

Amongst other routes, a mixture of compounds (2) and (4) or a mixture ofcompounds (3) and (5) of the invention may be prepared as in Scheme 1but using enantiomerically pure alcohols (IIa) and (IIb) as startingmaterials.

The intermediates of formula (IIa) and (IIb) can be prepared as singleenantiomers from the racemic alcohol (II) by one or more of thefollowing procedures (Scheme 2):

-   -   a) HPLC chiral chromatography separation using chiral columns        available in the market.    -   b) Enzymatic resolution treating the isomeric mixture with an        enzyme, such as lipase, which will acetylate one of the isomers        leaving the other isomer unreacted. The two isomers can than be        readily separated.    -   c) By treating the isomeric mixture with resolving reagents and        separating the resulting diastereoisomers by crystallization or        by ordinary column chromatography.

An alternative method to prepare intermediates (IIa) and (IIb) as singleenantiomers by chiral synthesis, treating a substrate of formula (I)with an appropriate chiral reducing agent known to those skilled in theart.

Yet another method to prepare mixtures (c)—comprising compound (2) and(4)—and (d)—comprising compounds (3) and (5)—(scheme 3), includes theresolution of the racemic mixture VIII using the already describedmethods (chiral HPLC separation, enzymatic resolution, chiralresolution, etc) followed by double bond reduction in each of theenantiomers VIIIa and VIIIb.

Mixture (b) (comprising compounds of formula (4) and (5)) and mixture(a) (comprising compounds of formula (2) and (3)) of the invention maybe prepared by asymmetric hydrogenolysis of a compound of formula VIusing for example Rhodium or Iridium catalysts in the presence of chiralligands as shown on Scheme 4. Chiral reduction of the double bond mayalso be performed using biocatalysts (e.g. Rhodotorula rubra andRhodotorula glutinis).

Compounds of formula (2), (3), (4) and (5) may be obtained from mixtures(c) and (d) (Scheme 45) by chiral HPLC separation. Alternatively, thedesired enantiomerically pure compounds can be prepared by chiralsynthetic procedures known to those skilled in the art (for example:asymmetric hydrogenolysis of the corresponding single isomer of compoundVI).

Abbreviations:

-   -   ACE: Angiotensin-converting enzyme    -   ADME: Absorption, distribution, metabolism and excretion    -   ALS: Amyotrophic lateral sclerosis    -   AMN: Adrenomyeloneuropathy    -   AUC: Area under the curve    -   C57BL/6 mouse: C57 black 6 mouse    -   cALD: cerebral variant of ALD    -   cAMN: Cerebral adrenomyeloneuropathy    -   CD20: B-lymphocyte antigen CD20    -   CD25: the alpha chain of the IL-2 receptor    -   CD52: Cluster of differentiation 52    -   cDNA: Complementary deoxyribonucleic acid    -   Cmax: Peak plasma concentration after administration.    -   COMT: Catechol O-methyltransferase    -   DEAD: Diethyl azadicarboxylate    -   EC₅₀: Half maximal effective concentration    -   hERG: human Ether-a-go-go-Related Gene    -   HPLC: High performance liquid chromatography    -   LLOQ: Lower limit of quantification    -   MAO-B: Monoamine oxidase B    -   mtDNA: mitochondrial deoxyribonucleic acid    -   NMDA: N-Methyl-D-aspartic acid    -   nDNA: nuclear deoxyribonucleic acid    -   NS: Nervous system    -   Ph: phenyl    -   PPARγ: Peroxisome proliferator-activated receptor-gamma    -   qPCR: Quantitative polymerase chain reaction    -   TIA: Transient ischaemic attack    -   Tmax: Time to reach Cmax    -   VSS: Aparent volume of distribution at steady state    -   X-ALD: X-linked adrenoleukodystrophy

The following examples support the invention.

Example 1: Pharmacokinetic Profile and Brain Distribution

Protocol: Pharmacokinetic parameters and brain distribution of5(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione(racemate or stereoisomers) following single oral (4.5 mg/kg) andintravenous (1 mg/kg) dose administration to male C57 BL/6 mice weredetermined. Blood samples and brain samples were collected pre-dosingand different times post dosing for both oral and i.v pharmacokinetics.All samples were processed for analysis by protein precipitation usingacetonitrile and analyzed with fit-for-purpose LC/MS/MS method. Thelower limit of quantification (LLOQ) in plasma and brain for5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione(1) is 0.99 ng/mL. Pharmacokinetic parameters were calculated using thenon-compartmental analysis tool of Phoenix WinNonlin.

The results from these experiments are shown in FIG. 1, FIG. 2 and FIG.3. The data clearly demonstrates that5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione(1) exhibits a good pharmacokinetic profile, low systemic plasmaclearance and acceptable Volume of Distribution (Vss) with abrain-plasma ratio exposure of 0.12.

Following a single intravenous administration of racemic5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione(FIG. 1) to C57BL/6 mice at 1 mg/kg dose, the compound exhibited lowsystemic plasma clearance (11.79 mL/min/kg, normal liver blood flow inmice=90 mL/min/kg) with terminal elimination plasma half-life of 1.79hr. The V_(ss) was 2-fold higher than the normal volume of total bodywater (0.7 L/kg).

After a single oral administration of racemic5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione(1) to C57BL/6 mice at 4.5 mg/kg dose (FIG. 2), plasma concentrationswere observed until 24 hr (1 animal). The Tmax in plasma was 0.50 hr.The oral bioavailability was 85%.

FIG. 3 shows that brain concentrations for both intravenous and oralpharmacokinetic profiles were observed until 8 hr. Tmax in brain is 0.50hr with brain-to-plasma exposure (AUClast) ratio of 0.12.

These results indicate that5-(4-(2-(50(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dionehas a favourable pharmacokinetic profile including good oralbioavailability and a brain-to-plasma exposure ratio of 0.12, thus thecompound meaningfully crosses the blood brain barrier.

Example 2: Mechanism of Action: in Vitro Pharmacology

Protocol: To determine the mechanism of action through the agonism ofPPAR gamma, a cellular functional assay was performed using a humanrecombinant cell line cotransfected with a PPRE luciferase reporter,PPAR-γ, RXR-α and coactivator DRIP205.

Transferred cells were treated with increasing doses of compounds.Luciferase activity was detected by alphascreen technology andnormalized based on β-galactosidase activity. The results are expressedas the fold induction over the control (Rosiglitazone 10 μM). Doseresponse curves were obtained. Results were calculated as EC₅₀ that isthe concentration of compound that provokes 50% control agonistresponse.

EC₅₀ racemic5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione=9.3μM

The results from these experiments indicate that racemic5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dioneand its stereoisomers have varying PPAR gamma agonists activities, witha range of EC₅₀s. These data show that these compounds activate PPARgamma receptors and consequently the biological functions depending onthis activation.

Example 3 General Experimental Conditions

¹H spectra were recorded on 400 MHz Varian NMR spectrometer usingappropriate deuterated solvents. Chromatographic analyses of thecompounds were conducted using appropriate methods as shown below.

LCMS Method

Column: Agilent Zorbax 3.5 μm, SB-C8 (4.6×75 mm); wavelength: 210 nm;flow: 1 mL/min; run time: 7 min; mobile phase-gradient (t/%B): 0/30,3.5/95, 5/95, 5.5/30, 7/30 [A: Water (0.1% formic acid); B:Acetonitrile]; MASS: Agilent-single quad-multimode-APCI-ESI.

Chiral HPLC Method

Column: Chiralpak-IA 5 μm (4.6 mm×250 mm); wavelength: 210 nm; flow: 0.7mL/min; run time: 30 min; mobile phase-isocratic: 65/35 (A/B) [A:n-Hexane (0.05% triethylamine and 0.1% trifluoracetic acid), B:Isopropyl alcohol].

Chiral Prep-HPLC Method

Column: Chiralpak-IA 5 μm (250×20 mm); wavelength: 254 nm; flow: 18ml/min; run time: 60 min; mobile phase-isocratic 50/50 (A/B): A:n-Hexane, B: EtOH (0.05% triehylamine).

HPLC Method

Column: Symmetry Shield RP-18, 5 μm (4.6×250 mm); wavelength: 210 nm;flow: 1 mL/min; run time: 28 min; mobile phase-gradient (t/%B): 0/10,8/10, 12/60, 16/80, 20/80, 24/10, 28/10 [A: Water (potassium dihydrogeno-phosphate (pH˜3)), B: Acetonitrile]

Example 4:5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione(1) was Prepared According to Scheme 6

1-(6-methyl-pyridin-3-yl)-ethanol (II)

LiHMDS (1.0 M in tetrahydrofurane, 463 ml, 0.463 mol) was added dropwise to a cooled solution of methyl 6-methylnicotinate (20 g, 0.132 mol)and ethyl acetate (82 g, 0.927 mol) in dimethylformamide at −50° C.;gradually raised the temperature to r.t. and stirred at the sametemperature. After 1 h, the reaction mixture was cooled to 0° C.; slowlydiluted with 20% sulphuric acid and heated to reflux. After 4 h, thereaction mixture was cooled to r.t. and further to 0° C. and basifiedwith potassium carbonate. The reaction medium was diluted with water andextracted in ethyl acetate (3×50 ml). Combined organic extract was driedover sodium sulphate and concentrated to afford crude1-(6-methylpyridin-3-yl)ethan-1-one (compound I) (20.0 g) which wastaken to next step without any purification.

ES-MS [M+1]+: 136.1

Sodium borohydride (2.3 g, 0.06 mol) was added in small portions over 30min. to a solution of compound I (16.4 g, 0.121 mol) in ethanol (160 ml)at 0° C. and the reaction mixture was stirred at same temperature. After1 h, the reaction mixture was diluted with sodium bicarbonate solution(sat) (2×200 ml) and extracted with dichloromethane (2×500 ml). Thecombined organic extract was dried over anhydrous sodium sulphate andconcentrated to afford a pale yellow oil, which was purified by flashcolumn chromatography (5% methanol/dichloromethane) to afford compoundII (17.0 g; 93% yield over 2 steps) as a pale yellow oil.

ES-MS [M+1]+: 138.1

¹H NMR (400 MHz, CDCl₃): δ 8.35 (d, J=2.0 Hz, 1H), 7.63 (dd, J=8.0, 2.4Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 4.89 (q, J=6.5 Hz, 1H), 3.30 (brs, 1H),2.50 (s, 3H), 1.48 (d, J=6.5 Hz, 3H)

5-(1-methoxymethoxy-ethyl)-2-methyl-pyridine (III)

Compound II (15 g, 0.109 mol) was added, drop wise, to a cooledsuspension of sodium hydride (6.56 g, 0.164 mol) in tetrahydrofurane(150 ml) and stirred at 0° C. After 30 min, chloromethyl methyl ether(13.2 g, 0.164 mol) was added drop wise while stirring and keeping theinternal temperature around 0° C. After addition is over, the reactionmixture was stirred at the same temperature for 1 h. The reaction wasquenched with ice cold water (80 ml) and extracted with ethyl acetate(3×50 ml). The combined organic extract was dried over anhydrous sodiumsulphate and concentrated to afford an orange color oil, which waspurified by flash column chromatography (1% methanol/dichloromethane) toafford compound III (10.0 g; 51% yield) as a pale yellow oil.

ES-MS [M+1]+: 182.2

¹H NMR (400 MHz, CDCl₃): δ 8.45 (d, J=2.0 Hz, 1H), 7.56 (dd, J=8.0, 2.0Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 4.75 (q, J=6.4 Hz, 1H), 4.57 (ABq, 2H),3.36 (s, 3H), 2.53 (s, 3H), 1.48 (d, J=6.6 Hz, 3H)

2-[5-(1-methoxymethoxy-ethyl)-pyridin-2-yl]-ethanol (IV)

A mixture of compound III (7.0 g, 0.0386 mol) and 37% formaldehydesolution (5.8 g, 0.077 mol) was heated to 160° C. in a sealed glass tubefor 5 h. The reaction mixture was cooled to r.t. and concentrated underreduced pressure to afford a crude compound which was purified by flashcolumn chromatography (1% methanol/dichloromethane) to afford compoundIV (1.2 g; 17% yield) as pale yellow oil.

ES-MS [M+1]+: 212.1

¹H NMR (400 MHz, CDCl₃): δ 8.42 (d, J=2.0 Hz, 1H), 7.65 (dd, J=8.0, 2.4Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 4.72 (q, J=6.6 Hz, 1H), 4.65 (t, J=5.6Hz, 1H), 4.52 (ABq, 2H), 3.73 (m, 2H), 3.24 (s, 3H), 2.86 (t, J=7.2 Hz,2H), 1.49 (d, J=6.4 Hz, 3H).

4-{2-[5-(1-methoxymethoxy-ethyl)-pyridin-2-yl]-ethoxy}-benzaldehyde (V)

Methanesulphonylchloride (1.19 g, 0.01 mol) was added, drop wise, to acooled suspension of compound IV (1.7 g, 0.008 mol) and triethylamine(1.79 ml, 0.013 mol) in dichloromethane (20 ml) at 0° C. and stirred atsame temperature for 1 h. The reaction mixture was diluted with water(50 ml) and extracted with dichloromethane (3×50 ml). The combinedorganic extract was dried over anhydrous sodium sulphate andconcentrated to afford 2-(5-(1-(methoxymethoxy)ethyl)pyridin-2-yl)ethylmethanesulfonate (2.04 g; 88% yield) as a yellow oil, which was taken tonext step without purification.

ES-MS [M+1]+: 290

2-(5-(1-methoxymethoxy)ethyl)pyridin-2-yl)ethyl methanesulfonate wasadded (2.3 g, 0.008 mol) to a stirred suspension of4-hydroxybenzaldehyde (1.65 g, 0.0137 mol) and potassium carbonate (1.86g, 0.0137 mol) in mixture of toluene (25 ml) and ethanol (25 ml);stirred at 85° C. for 5 h. After consumption of the starting materials,the reaction mixture was diluted with water (30 ml) and extracted withethyl acetate (2×100 ml). The combined organic extract was washed withwater; dried over anhydrous sodium sulphate and concentrated to afford acrude dark yellow liquid. The crude was purified by flash columnchromatography (1% methanol/dichloromethane) to afford compound V (1.5g; 60% yield) as pale yellow liquid.

ES-MS [M+1]+: 316.1

5-(4-{2-[5-(1-methoxymethoxy-ethyl)-pyridin-2-yl]-ethoxy}-benzylidene)-thiazolidine-2,4-dione(VI)

Piperidine (80 mg, 0.95 mmol) was added to a solution of compound V (0.6g, 1.9 mmol) and thiazolidine-2,4-dione (0.22 g, 1.9 mmol) in ethanol(15 ml) and the mixture was heated to reflux overnight. After 15 h, thereaction mixture was cooled to r.t. and concentrated under reducedpressure to afford crude mixture, which was purified by flash columnchromatography (2% methanol/dichloromethane) to afford compound VI (500mg; 64% yield) as a yellow solid.

ES-MS [M+1]+: 415.1

¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (br s, 1H), 8.47 (d, J=2.0 Hz, 1H),7.70 (dd, L=8.0, 2.0 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.0 Hz,1H), 7.21 (d, J=8.8 Hz, 2H), 4.73 (m, 1H), 4.60-4.40 (m, 4H), 4.22 (t,J=6.2 Hz, 1H), 3.24 (s, 3H), 3.20 (t, J=6.8 Hz, 2H), 1.41 (d, J=6.0 Hz,3H).

5-(4-{(2-[5-(1-hydroxy-ethyl)-pyridine-2-yl]-ethoxy}-benzyl)-thiazolidine-2,4-dione(1)

A solution of sodium borohydride (115 mg, 3.017 mmol) in 0.2N sodiumhydroxide (1.2 ml) was added slowly to a stirred solution of compound VI(0.5 g, 1.207 mmol), dimethylglyoxime (42 mg, 0.36 mmol) and CoCl₂.6H₂O(23 mg, 0.096 mmol) in a mixture of water (6 ml); tetrahydrofurane (6ml) and 1M sodium hydroxide (1 ml) solution at 10° C. and afteraddition, the reaction mixture was stirred at r.t. After 1 h, thereaction color lightened and additional quantities of sodium borohydride(46 mg, 1.207 mmol) and CoCl₂.6H₂O (22 mg, 0.096 mmol) were added andstirring was continued at r.t. After 12 h, the reaction was neutralizedwith acetic acid (pH˜7); diluted with water (10 ml) and extracted inethyl acetate (3×50 ml). The combined organic extract was dried overanhydrous sodium sulphate and concentrated to afford crude compound VII,5-(4-(2-(5-(1-(methoxymethoxy)ethyl)pyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione(0.4 g) as pale yellow semi solid, which was taken to next step withoutpurification.

ES-MS [M+1]+: 417.5

2N HCl (2 ml) was added to a solution of compound VII (0.4 g, 0.96 mmol)in methanol (20 ml) and the mixture was heated to reflux. After 4 h, thereaction mixture was cooled to r.t.; concentrated under reduced pressureto afford a residue which was dissolved in water and the solution wasneutralized using sodium bicarbonate solution (sat). The resulting whiteprecipitate was collected by filtration to afford compound 1 (250 mg;56% yield over 2 steps) as an off-white solid.

ES-MS [M+1]+: 373.4

¹H NMR (400 MHz, DMSO-d₆): δ12.00 (br s, —NH), 8.46 (d, J=2.0 Hz, 1H),7.66 (dd, J=8.0, 2.4 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.4 Hz,2H), 6.86 (d, J=8.4 Hz, 2H), 5.25 (d, J=4.4 Hz, 1H), 4.86 (m, 1H), 4.75(m, 1H), 4.30 (t, J=6.8 Hz, 2H), 3.30 (m, 1H), 3.14 (t, J=6.4 Hz, 2H),3.04 (m, 1H), 1.34 (d, J=6.4 Hz, 3H).

Example 5 (Mixture (c) of Compounds (2) and (4)) and (Mixture (c) ofCompounds (3) and (4))

A mixture of compounds (2) and (4) (mixture (c)) and a mixture ofcompounds (3) and (5) (mixture (d)) were prepared according to Scheme 7.

The methyl chloromethyl ether group of(Z)-5-(4-(2-(5-(methoxymethoxy)ethyl)pyridin-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione(compound VI) was removed by treatment with aqueous HCl to give theracemic alcohol VIII.

The enantiomers contained in the racemic mixture of(Z)-5-(4-(2-(5-(1-hydroxyethyl)pyridin-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione(VIII) were separated by HPLC chiral chromatography to yield (R)-VIIIand (S)-VIII.

(R)-VIII was then treated with a reducing mixture (CoCl₂-6H₂O,dimethylglyoxime, NaOH, sodium borohydride), (modified conjugatereduction protocol of Pfaltz), to yield mixture (c) comprising compounds(2) and (4).

(S)-VIII was then treated with a reducing mixture (CoCl₂-6H₂O,dimethylglyoxime, NaOH, sodium borohydride), (modified conjugatereduction protocol of Pfaltz), to yield mixture (d) comprising compounds(3) and (5).

Example 6: Preparation of Diastereomeric Mixtures D-1 and D-2 of M-IV

Step 1: Synthesis of compound VIII: HCl (48 ml, 2N) was added to asolution of compound VI (10 g, 0.024 mol) in methanol (200 ml) and themixture was heated to reflux. After 4 h of reflux, the reaction mixturewas cooled to r.t. and concentrated under reduced pressure to afford ayellow solid. The solid was suspended in water (70 ml) and neutralizedusing a saturated NaHCO₃ solution. The resulting pale yellow precipitatewas collected by filtration and vacuum dried to afford compound VIII(7.5 g; 84% yield).

ES-MS [M+1]⁺: 371.0.

Step 2: Chiral Prep. HPLC

Compound VIII (1.0 g) was dissolved in a mixture containing equalvolumes of acetonitrile, methanol and dichloromethane; injected (150 μlinjections) in chiral prep-HPLC column (Chiralpak-IA 250×20 mm, 5micron) and separated [Mobile phase-n-Hexane/0.05% Et₃N in EtOH (50:50);flow Rate: 18 ml/min; run time: 60 min]. The fractions containing theenantiomers VIIIa and VIIIb were separately concentrated under reducedpressure to minimum volume and the respective residues were diluted withEtOAc (100 ml), followed by water (50 ml). The resultant organic phaseswere dried over anhydrous Na₂SO₄ and concentrated to afford compoundsVIIIa and VIIIb as off-white solids. Enantiomers VIIIa and VIIIb wereisolated but the absolute configuration of each enantiomer has not beendetermined.

Compound Ent-1 (VIII): 250 mg (Yield: 50%); t_(T) (Chiral HPLC)=14.8min; ES-MS [M+1]⁺: 371.0; ¹H NMR (400 MHz, DMSO-d₆): δ 12.5 (br S, 1H),8.47 (s, 1H), 7.71 (s, 1H), 7.67 (dd, J=8.0, 2.0 Hz, 1H), 7.53 (d, J=9.2Hz. 2H), 7.31 (d, J=7.6 Hz, 1H), 7.08 (d, J=8.8 Hz, 2H), 5.25 (d, J=4.0Hz, 1H), 4.74-4.76 (m, 1H), 4.43 (dd, J=6.8, 6.4 Hz, 2H), 3.18 (t, J=6.4Hz, 2H), 1.34 (d, J=6.4 Hz, 3H).

Compound Ent-2 (VIII): 237 mg (Yield: 47%): t_(R) (Chiral HPLC)=16.7min; ES-MS [M+1]⁺: 371.0; ¹H NMR (400 MHz, DMSO-d₆): δ 12.5 (br S, 1H),8.47 (s, 1H), 7.71 (s, 1H), 7.67 (dd, J=8.0, 2.0 Hz, 1H), 7.53 (d, J=8.8Hz, 2H), 7.31 (d, J=8.0 Hz, 1H), 7.08 (d, J=9.2 Hz, 2H), 5.23 (d, J=3.6Hz, 1H), 4.75 (m, 1H), 4.43 (dd, J=6.8, 6.4 Hz, 2H), 3.18 (dd, J=6.8,6.4 Hz, 2H), 1.34 (d, J=6.4 Hz, 3H).

Synthesis of Diastereomeric Mixtures of M-IV Synthesis of D-1 MIV

Step 3: A solution of NaBH₄ (77 mg, 2.02 mmol) in 0.1 N NaOH (2 ml) wasadded slowly to a stirred solution of compound Ent-1 (VIII) (250 mg,0.675 mmol), dimethylglyoxime (32 mg, 0.27 mmol) and CoCl₂.6H₂O (16 mg,0.067 mmol) in a mixture of water (10 ml), THF (10 ml) and 1M NaOH (0.5ml) solution at 10° C., and the reaction mixture was stirred at r.t. for1 h. After color of the reaction medium faded, additional quantity ofNaBH₄ (26 mg, 0.675 mmol) and CoCl₂.6H₂O (16 mg, 0.067 mmol) were addedand stirring was continued at r.t. [additional quantities of CoC₁₂ andNaBH₄ were added at 12 h intervals till the starting material wasconsumed, as monitored by LCMS]. After 90-96 h, the reaction mixture wasneutralized with AcOH (pH˜7); diluted with water (10 ml) and extractedin EtOAc (3×50 ml). The combined organic extract was dried overanhydrous Na₂SO₄ and concentrated to afford crude compound which waspurified by flash column chromatography (SiO₂; 4% methanol in CH₂Cl₂) toafford diastereomeric mixture of MIV D-1 (125 mg) as off-white solid.

Synthesis of D-2 MIV

Step 3: A solution of NaBH₄ (72 mg, 1.921 mmol), in 0.1 N NaOH (2 ml)was added slowly to a stirred solution of compound Ent-2 (VIII) (237 mg,0.64 mmol), dimethylglyoxime (30 mg, 0.256 mmol) and CoCl₂.6H₂O (15 mg,0.064 mmol) in a mixture of water (10 ml), THF (10 ml), and 1M NaOH (0.5ml) solution at 10° C., and the reaction mixture was stirred at r.t. for1 h. After color of the reaction medium faded, additional quantity ofNaBH₄ (24 mg, 0.64 mmol) and CoCl₂.6H₂O (15 mg, 0.064 mmol) were addedand stirring was continued at r.t. [additional quantities of CoCl₂.6H₂Oand NaBH₄ were added at 12 h intervals till the starting material wasconsumed, as monitored by LCMS]. After 96 h, the reaction mixture wasneutralized with AcOH (pH˜7); diluted with water (10 ml) and extractedin EtOAc (3×50 ml). The combined organic extract was dried overanhydrous Na₂SO₄ and concentrated to afford crude compound, which waspurified by flash column chromatography (SiO₂; 4% methanol in CH₂Cl₂) toafford diastereomeric mixture of MIV D-2 (100 mg) as off-white solid.

MIV D-1: yield: 125 mg (50%); t_(R) (Chiral HPLC)=17.8, 14.7 min; ES-MS[M+1]⁺: 373.0, ¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (br s, NH), 8.46 (d,J=2.0 Hz, 1H), 7.67 (dd, J=8.0, 2.4 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H),7.13 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 5.27 (d, J=4.0 Hz, 1H),4.88-4.85 (m, 1H), 4.76-4.74 (m, 1H), 4.30 (t, J=6.8 Hz, 2H), 3.30 (m,1H), 3.14 (dd, J=6.8, 6.4 Hz, 2H), 3.08-3.02 (m, 1H), 1.34 (d, J=6.4 Hz,3H).

MIV D-2: yield; 100 mg (42%); t_(R) (Chiral HPLC)=19.4, 16.5 min; ES-MS[M+1]⁺: 373.0; ¹H NMR (400 MHz, DMSO-d₆): δ 12.01 (br s, —NH), (d, J=2.0Hz, 1H), 7.67 (dd, J=8.0, 2.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.13 (d,J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.27 (d, J=4.0 Hz, 1H), 4.88-4.85(m, 1H), 4.76-4.74 (m, 1H), 4.30 (dd, J=6.8, 6.4 Hz, 2H), 3.30 (m, 1H),3.14 (dd, J=6.8, 6.4 Hz, 2H), 3.08-3.02 (m, 1H), 1.34 (d, J=6.8 Hz, 3H).

Diastereomeric mixtures D-1 and D-2 of MIV correspond to mixtures (c)and (d) described above, but the specific diastereomers present in eachdiastereomeric mixture have not been assigned.

Example 7: In Vitro ADME and Toxicological Characterization

Protocol: The assays performed include cytochrome P450 inhibition withthe different isoforms, microsomal and hepatocyte stability,neurotoxicity in neural cells and hERG safety assays using a patch clampelectrophysiology measurement (FDA Draft Guidance for Industry, DrugInteraction Studies—Study Design, Data Analysis, Implications forDosing, and Labelling Recommendations 2012, The European MedicinesAgency (EMA) Guideline on the Investigation of Drug Interactions Adoptedin 2012, Schroeder K et al. 2003 J Biomol Screen 8 (1); 50-64, Barter ZE et al. 2007 Curr Drug Metab 8 (1); 33-45, LeCluyse E L and Alexandre E2010 Methods Mol Biol 640; 57-82). The results indicate a safe andfavourable ADME profile for the compounds of the invention.

Example 8: The brain Plasma Ratios of Pioglitazone, MIV, MIII and MIIFollowing Oral Dosing of a Single Administration of Pioglitazone at 4.5mg/kg in Male C57BL/6 Mice

The brain-plasma ratio was calculated based on levels of Pioglitazone,MIV, MIII and MII in plasma and brain quantified at C max (maximalconcentration) following oral dosing of a single administration ofPioglitazone at 4.5 mg/kg in male C57BL/6 mice.

The percentage brain plasma ratio was 9, 13, 7 and 1%, respectively, forPioglitazone, MII and MIII as shown in the FIG. 4. Thus, activemetabolites MIII and MII crossed the BBB at much lower extent thanPioglitazone as it was predicted based on the physicochemical propertiesof the compounds (see Table 1). In contrast, unexpectedly metabolite MIVcrossed the BBB in a higher percentage than the parent compoundPiolgitazone

The calculations of the both indexes (ClogP and QPlogBB) forPioglitazone and its metabolites MII and MIII are shown in Table 1. Forboth indexes the 2 metabolites are lower than for pioglitazone,suggesting for MII, and MIII a less favored penetration and distributionwithin CNS.

TABLE 1 Structure Name QPlogBB CLogP HBD HBA

Pioglitazone −1.22 3.53 1 4

MIV −1.72 1.78 2 5

MIII −1.66 2.34 1 5

MII −1.72 2.13 2 5

Example 9: The Brain Plasma Ratios of Pioglitazone and MIV and FollowingOral Dosing of a Single Administration of Either Pioglitazone or M-IVBoth at 4.5 mg/kg in Male C57BL/6 Mice

In order to confirm the findings showed in the last example, additionalexperiments were done. The brain-plasma ratio was calculated based onthe pharmacokinetics curves of plasma and brain concentration-timeprofiles calculated as area under the curves of Pioglitazone andfollowing oral dosing of a single administration of either Pioglitazoneor MIV both at 4.5 mg/kg in male C57BL/6 mice.

The percentage brain-plasma ratio was 8% and 12% for Pioglitazone and M4respectively as shown in the FIG. 5. This 50% of increase inbrain-plasma ratio for the hydroxilated metabolite M-IV compared withthat the one observed with Pioglitazone under the same condition, wastotally unexpected based on the on the physicochemical propertiespredictive calculations (see Table 1).

M-IV shows a behavior contrary to that expected. As MII, MIV is amonohydroxylated metabolite, but instead of decreasing around 50% itsBBB penetration, the BBB penetration is 50% higher.

The calculations of the both indexes (ClogP and QPlogBB) forPioglitazone and M-IV are shown in Table 1. For both indexes MIV shows alower value than pioglitazone, suggesting for M-IV a less favoredpenetration and distribution within CNS, contrary to what hassurprisingly been observed experimentally.

Example 10: Characterization of in Vivo Epimerization of the TwoDiastereomeric Mixtures of MIV, D-1 and D-2 in Mice

Protocol: Pharmacokinetic parameters of diastereomeric mixtures D-1 andD-2 of5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ehtoxy)benzyl)thiazolidine-2,4-dionefollowing single oral (4.5 mg/kg) gavage dose administration to maleSwiss albino mice were determined. A total of 51 mice were used in thisstudy with parallel sampling design (n=3/time point). Blood samples andwere collected pre-dosing and different times post dosing for both oralpharmacokinetics.

Diastereomeric mixtures D-1 and D-2 of5(4-(2-(5(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dionewere extracted from Swiss albino mouse plasma samples usingliquid-liquid extraction (LLE) method and quantified using liquidchromatography tandem mass spectrometry (LC-MS/MS) with Electro SprayIonization (ESI) and multiple reaction monitoring (MRM). Selected plasmaand brain samples were subjected for the chiral analysis using ChiralAGP column to identify the chiral inter-conversion. Achiralbioanalytical method was employed to quantify the total M-IV present inthe plasma and brain samples.

Formulation samples were suitably diluted with 70% methanol and theinstrument response was compared against known correspondingdiastereomeric mixture standard using achiral LC-MS/MS method. The lowerlimit of quantification (LLOQ) in plasma for diastereomeric mixture D-1and D-2 of5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione(1) is 0.90 ng/mL. Pharmacokinetic parameters were calculated using thenon-compartmental analysis tool of Phoenix WinNonlin.

The results from these experiments are shown in FIG. 6. The data clearlydemonstrates that the difference in % of conversion among diastereomericmixtures is high in mice. In vivo, both D-1 and D-2 interconvert,although the conversion to D-2 from D-1 is much more accentuated thanthe conversion from D-1 to D-2.

Example 11: Characterization of Cortical Neurons Glutamate Injured as aModel of Alzheimer's Disease

Primary cortical neurons injured by glutamate (excitotoxicity) are awell established in vitro model for neurodegenerative disorders (JNeurosci; 1999 Apr. 1; 19(7):2455-63; J Neurosci Res. 2013 May;91(5):706-16) such as Parkinson's disease, Alzheimer's disease, andHuntington's disease (Brain Res Bull 2013 April; 93:27-31.), but also inother pathologies such as multiple sclerosis (Scand J Immunol 2014;79(3):181-186).

Protocol: Rat cortical neurons were cultured as described by Singer (JNeurosci. 1999 Apr. 1; 19(7):2455-63) and Callizot (J Neurosci Res. 2013May; 91(5):706-16).

Foetuses were collected and immediately placed in ice-cold Leibovitzmedium. Cortex was treated with a trypsin-EDTA solution and thedissociation was stopped by addition of Dulbecco's modified Eagle'smedium (DMEM) with glucose (Pan Biotech), containing DNAse I and 10%fetal calf serum (FCS). Cells were mechanically dissociated andcentrifuged. The pellet was resuspended in a defined culture medium with10 ng/ml of brain-derived neurotrophic factor (BDNF). The cells wereseeded in 96-well plates precoated with poly-L-lysine and were culturedat 37°. The medium was changed every 2 days. The cortical neurons wereintoxicated with glutamate after 13 days of culture.

Briefly, on day 13 of culture, BDNF and test compound were pre-incubatedwith primary cortical neurons for 1 hour before glutamate exposure.Glutamate was added to a final concentration of 40 μM diluted in controlmedium in presence of BDNF or test compound for 20 min.

After 20 min, glutamate was washed out and fresh culture medium withBDNF or test compound was added for additional 48 hours. The survivalevaluation was done by a MTT assay performed with CellTiter 96® AqueousOne Solution Cell Proliferation Assay (Promega).

The results are shown in FIG. 7. They show that on a glutamate injury,MIV (compound (1)) shows a protective effect (reaching the significancefor the 3 μM). Interestingly we observed a nice bell shape curve forMIV. At 3 μM we have a full protective effect as the one observed withthe reference compound (BDNF 50 ng/ml). All values are expressed asmean+/−SE. Statistical analysis was performed by one-way ANOVA, followedby Dunnett's or PLSD Fisher test. p<0.05 are considered significant.

Example 12: Characterization of Inhibition of MAO B (Monoamine Oxidases)as a Potential-Drug for Treating Parkinson's Disease

Selective inhibitors MAO-B increase dopamine levels in the CNS affectedin Parkinson's disease without increasing levels of the otherneurotransmisors (epinephrine, norepinephrine or serotonine), incontrast to no selective MAO inhibitors (MAO-A and MAO B). The MAO-Binhibitors can be used also to treat depressions.

Protocol: Human recombinant monoamine oxidase proteins MAO-A and MAO-Bwere purchased from Sigma Aldrich (Reference M7316 and M7441respectively). In order to monitor the MAO enzymatic activities andtheir inhibition rate a fluorescence based assay was used The substratefor the assay, kynuramine, is non-fluorescent until undergoing oxidativedomination by MAOs resulting in the fluorescent product4-hydroxyquinoline. Kynuramine is a substrate for both MAO-A and -B(non-specific substrate). Clorgiline and Deprenyl (Sigma Aldrich) wereused as controls for specific inhibition of MAO-A and MAO-Brespectively.

Results snow that5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dioneinhibits MAO B with a IC₅₀ of 70.5 nM. In contrast, this compound didnot inhibit MAO A protein.

Example 13: Characterization of in Vivo Efficacy in an Animal ModelExperimental Autoimmune Encephalomyelitis (EAE)as a Model ofNeuroinflammatory Diseases

Neuroinflammation can be initiated in response to a variety ofinfection, traumatic brain injury, toxics, or autoimmunity in the CNS.

The neuroinflammatory models are characterized by proliferation ofastrocytes and microglia, along with neuronal loss. Is a prominentfeature of many diseases of the central nervous system, includingAlzheimer's Disease, Multiple Sclerosis, stroke, Parkinson, traumaticbrain injury, infection and ALD (Human Molecular Genetics, 2004, Vol.13, No. 23 2997-3006).

Chronic inflammation is the sustained activation of glial cells andrecruitment of other immune cells into the brain. It is chronicinflammation that is typically associated with neurodegenerativediseases.

The EAE model is a neuroinflammatory model, classically used formultiple sclerosis, which resembles and includes most of the features ofthe severe cerebral forms of ALD, microglial activation, braindemyelination and axonal degeneration as well. Although the ethiology ofthe disease is different from ALD and the EAE (a model of multiplesclerosis triggered by autoreactive CD4+ lymphocytes), the EAE model isa valuable tool for studying therapies for both ALD and multiplesclerosis (Nature 2007; 7:904-912).

Protocol: The development of clinical symptoms in multiple sclerosis andits animal model experimental autoimmune encephalomyelitis (EAE)involves T-cell activation and migration into the central nervoussystem, production of glial-derived inflammatory molecules, anddemyelination and axonal damage. Chronic, monophasic EAE was activelyinduced as described with greater than 98% pure synthetic myelinoligodendrocyte glycoprotein peptide 35-55(MOG35-55,MEVGWYRSPFSRVVHLYRNGK, SEQ ID NO: 1). Female C57BL/6 mice (6-8 weeksold) were injected (two 100 μL subcutaneous injections into one hindlimb) with 250 μg of MOG35-55 emulsified in a 100 μL phosphate-bufferedsolution mixed with 100 μL of complete Freund's adjuvant containing 500μg of Mycobacterium tuberculosis (Difco, Detroit, Mich.). The micereceived an injection or pertussis toxin (400 ng in 200 μL of aphosphate-buffered solution, intraperitoneally), a second pertussistoxin injection 2 days later, and a booster injection of MOG35-55 at 7days. Clinical signs were scored as follows: 0, no signs; 1.0, limptail/loss of righting; 2.0, ataxia with limp tail; 3.0, paralysis ofsingle hind limb; 4.0, paralysis of both hind limbs; 4.5, moribund; and5.0, death. For both models, scores of 5 were noted and counted on theday of death only.

The compound was administered twice a day (bid) started on day 5 postimmunization for 15 days at three different increasing doses.

The results snowed that MIV (compound (1)) reduces the development andseverity of experimental autoimmune encephalomyelitis model. Averagedaily clinical scores from the experiment are shown in FIG. 9. Theclinical symptoms decreases in a dose-dependent manner, the highestdoses show the maximal effect. Clinical symptoms were reduced by MIV,suggesting a role for PPARgamma activation in protective effects. Nobody weight loss and no significant hematological toxicity at highestdoses associated to treatment.

Neuroinflammation is a hallmark of both multiple sclerosis and ALD, thusMIV may be effective on both diseases. In fact, decreasing microgliaactivation provides a molecular basis for explaining why allogeneic andautologous HSCT are effective at arresting the cerebral inflammation,namely by the replacement and the functional metabolic restoration ofthe monocyte lineage and connect cALD and AMN phenotypes with a sharedpathogenic pathway (Human Molecular Genetics, 2012, Vol. 21, No. 51062-1077). Thus, these models may be have a great potential andrelevance to study the role of PPAR gamma agonists in ALD.

Example 14: Characterization in Fibroblasts from Patients of X-ALD as aModel of X-Linked Adrenoleukodystrophy

Human control and X-linked adrenoleukodystrophy fibroblasts wereobtained from Coriell (Candem, USA). Cells were grown in Dulbecco'smodified Eagle medium containing 10% foetal bovine serum, 100 U/mlpenicillin and 100 mg streptomycin, at 37° C. in humidified 95% air/5%CO2, to 80-90% confluence. To perform our experiments, Dulbecco'smodified Eagle medium without D-glucose, pyruvate or L-glutamine wasused. Cells were cultured in this medium supplemented with 1 g/l ofglucose or 1 g/l of galactose and 10% foetal bovine serum for 24 hoursincubated with increasing doses of MIV (3, 10 and 30 μM).

The determination of MTT was performed as described by Mosmann J.Immunol. Methods 1983, 65,55-63 and by Hansen J. Immunol. Methods 1989:119,203-210. This method is based on the ability of viable but not deadcells to convert the tetrazolium salt (MTT) to colored formazan.

For the determination of ATP levels, 2×10⁴ cells/well were seeded in 96well cell culture plate in complete medium. After 16-18 h cells, werelysed in 20 μl lysis buffer and 10 μl of lysate was used to measure ATPlevels using ATP determination Kit (Molecular Probes, Invitrogen). 1 μleach of the remaining lysate was used for protein measurement.

Results show a protective effect of MIV (compound (1)) on ALDfibroblasts based on increase in cell survival (20% at 3, μM, vsnon-treated).

Example 15: Characterization of Spinal Cord Motor Neurons as a Model ofMotor Neuron Diseases (ALS)

Spinal cord motor neurons injured by glutamate are an in vitroexperimental model suitable for studying ALS and other motor neurondiseases (MNDs) such as Progressive bulbar palsy, pseudobulbar palsy,primary lateral sclerosis (PLS), progressive muscular atrophy, spinalmuscular atrophy (SMA), post-polio syndrome (PPS) and other rarediseases such as Charcot-Marie-Tooth disease, Guillain-Barré syndrome orAMN (Neuron. 1992 April; 8(4);737-44).

Protocol: Rat spinal cord (SC) motor neurons were cultured as describedby Martinou (Neuron. 1992 April; 8(4):737-44) and Wang (PLoS Genet.2013; 9(9)). Briefly, pregnant female rats of 14 days gestation werekilled by cervical dislocation and foetuses were collected andimmediately placed in ice-cold L15 Leibovitz medium. Spinal cord wastreated for 20 min at 37° C. with a trypsin-EDTA. The dissociation wasstopped by addition of Dulbecco's modified Eagle's medium (DMEM) withglucose (Pan Biotech), containing DNAse I and 10% fetal calf serum(FCS). Cells were mechanically dissociated and they were thencentrifuged. The pellet was resuspended in a defined culture medium with10 ng/ml of brain-derived neurotrophic factor (BDNF). The cells wereseeded in 96-well plates precoated with poly-L-lysine and were culturedat 37°. The medium was changed every 2 days.

Briefly, on day 13 of culture, BDNF or test compound was preincubatedwith primary Spinal cord (SC) motor neurons for 1 hour before glutamateexposure. Glutamate was added to a final concentration of 10 μ2M dilutedin control medium in presence of BDNF or test compound for 20 min. After20 min, glutamate was washed out and fresh culture medium with BDNF ortest compound was added for additional 48 hours.

The survival evaluation was done by immunostaining. 48 after theintoxication, the cell culture supernatant was taken off and the SCmotor neurons were fixed by a cold solution of ethanol (95%) and aceticacid (5%) for 5 min and permeabilized. Cells were incubated for 2 hourswith a monoclonal antibody anti microtubule-associated-protein 2 (MAP-2)that stains specifically cell bodies of neurons (MAP-2) allowing studyof neuron survival evaluation in the culture. This antibody was revealedwith Alexa Fluor 488 goat anti-mouse IgG).

For each condition 6 wells were assessed, 30 pictures per well weretaken using ImageXpress (Molecular Device) with 20× magnification. Allimages were taken with the same conditions. Analysis of total number ofneurons was performed automatically by using Custom module editor(Molecular Device).

Test compounds were pre-incubated for 1 hour before glutamateapplication.

The results (FIG. 10) showed that MIV (compound (1), 1 μM) on aglutamate injury has a protective effect in SC motor neurons (MN),demonstrated by a statistically different (p<0.05 t Student's) increasein cell survival vs the control with glutamate (Glut).

1-27. (canceled)
 28. A method of treatment or prevention of a centralnervous system disorder, comprising administering to a subject in needthereof a dosage form comprising an effective amount of a compound offormula (1)

or a pharmaceutically acceptable salt thereof, wherein the centralnervous system disorder is selected from the group consisting of aneurodegenerative disease, a cerebrovascular disease, seizure, epilepsy,a viral disease, a neuroinflammatory disease, a brain tumour, atraumatic brain injury, and a rare metabolic disease.
 29. The methodaccording to claim 28, wherein the compound of formula (1) is: (2)(R)-5-(4-(2-(5-((R)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;(3)(R)-5-(4-(2-(5-((S)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;(4)(S)-5-(4-(2-(5-((R)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;or (5)(S)-5-(4-(2-(5-((S)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;or a pharmaceutically acceptable salt thereof.
 30. A method of treatmentor prevention of a central nervous system disorder, comprisingadministering to a subject in need thereof an effective amount of amixture of two or more compounds selected from the group consisting ofcompound (2):(R)-5-(4-(2-(5-((R)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;compound (3):(R)-5-(4-(2-(5-((S)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;compound (4):(S)-5-(4-(2-(5-((R)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;and compound (5):(S)-5-(4-(2-(5-((S)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;or a pharmaceutically acceptable salt thereof. wherein the mixture isoptically active, and wherein the central nervous system disorder isselected from the group consisting of a neurodegenerative disease, acerebrovascular disease, seizure, epilepsy, a viral disease, aneuroinflammatory disease, a brain tumour, a traumatic brain injury, anda rare metabolic disease.
 31. The method according to claim 30, whereinthe mixture comprises (a) said compound (2) and said compound (3), or apharmaceutically acceptable salt thereof; or (b) said compound (4) andsaid compound (5), or a pharmaceutically acceptable salt thereof; or (c)said compound (2) and said compound (4), or a pharmaceuticallyacceptable salt thereof; or (d) said compound (3) and said compound (5),or a pharmaceutically acceptable salt thereof.
 32. The method accordingto claim 28, wherein the rare metabolic disease is selected from thegroup consisting of organic acidemias, fatty acid disorders and geneticmitochondrial disorders.
 33. The method according to claim 28, whereinthe central nervous system disorder is a neurodegenerative disease. 34.The method according to claim 33 wherein the the neurodegenerativedisease is selected from the group consisting of Alzheimer's disease,Huntington's chorea, degenerative ataxia, multiple system atrophy,leukodystrophy, and a motor neuron disease.
 35. The method according toclaim 34, wherein the neurodegenerative disease is a leukodystrophy. 36.The method according to claim 28, wherein the central nervous systemdisorder is a cerebrovascular disease. 37-38. (canceled)
 39. The methodof claim 36, wherein the cerebrovascular disease is selected from thegroup consisting of global or local ischemia, intracerebral haemorrhage,stroke, vascular dementia.
 40. The method according to claim 28, whereinthe central nervous system disorder is a neuroinflammatory disease. 41.The method of claim 34, wherein the motor neuron disease is selectedfrom the group consisting of progressive bulbar palsy, pseudobulbarpalsy, primary lateral sclerosis (PLS), progressive muscular atrophy,spinal muscular atrophy (SMA), post-polio syndrome (PPS)-Marie-Toothdisease, Guillan-Barré syndrome, and adrenomyeloneuropathy (AMN). 42.The method of claim 28, wherein the central nervous system disorder isseizure or epilepsy.
 43. The method of claim 28, wherein the centralnervous system disorder is a viral disease.
 44. The method of claim 43,wherein the viral disease is selected from the group consisting ofmeningitis, encephalitis, rabies, measles, mumps, poliomyelitis, herpessimplex, and varicella zoster.
 45. The method of claim 28, wherein thecentral nervous system disorder is a brain tumor.
 46. The method ofclaim 46, wherein the brain tumour is located in the neurons or glialcells of the brain or is a metastasis of the primary brain tumour. 47.The method of claim 28, wherein the central nervous system disorder is atraumatic brain injury.
 48. The method according to claim 30, whereinthe central nervous system disorder is a neurodegenerative disease or acerebrovascular disease.
 49. The method according to claim 49, whereinthe neurodegenerative disease is selected from the group consisting ofAlzheimer's disease, Huntington's chorea, degenerative ataxia, multiplesystem atrophy, leukodystrophy, and a motor neuron disease.
 50. Themethod according to claim 28, wherein no more than 1% of the totalnumber of hydrogen atoms per mole of the compound of formula (1) are inthe form of the ²H isotope.
 51. The method according to claim 28,wherein the compound of formula (1) is administered to the subject in anoral dosage form.
 52. The method according to claim 52, wherein the oraldosage form is a solid oral dosage form, an oral solution, or an oralsuspension.
 53. The method according to claim 30, wherein no more than1% of the total number of hydrogen atoms per mole of each of the two ormore compounds in the mixture are in the form of the ²H isotope.
 54. Amethod of treatment or prevention of Friedreich's ataxia, comprisingadministering to a subject in need thereof a dosage form comprising aneffective amount of a compound of formula (1)

or a pharmaceutically acceptable salt thereof.